A miR-137-Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing.

BACKGROUND: miR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-wide association studies have implicated miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing. METHODS: Using RNA sequencing data from postmortem prefrontal cortex (N = 522), we identified a coexpression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of coexpression prediction and associated them with functional magnetic resonance imaging activation in healthy volunteers (n1 = 214; n2 = 136; n3 = 2075; n4 = 1800) and with short-term treatment response in patients with schizophrenia (N = 427). RESULTS: In 4652 human participants, we found that 1) schizophrenia risk genes were coexpressed in a biologically validated set enriched for miR-137 targets; 2) increased expression of miR-137 target risk genes was mediated by low prefrontal miR-137 expression; 3) alleles that predict greater gene set coexpression were associated with greater prefrontal activation during emotion processing in 3 independent healthy cohorts (n1, n2, n3) in interaction with age (n4); and 4) these alleles predicted less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia. CONCLUSIONS: The functional translation of miR-137 target gene expression linked with schizophrenia involves the neural substrates of emotion processing.

Hemispheric specialization in affective responses, cerebral dominance for language, and handedness: Lateralization of emotion, language, and dexterity.

Hemispheric specialization in affective responses has received little attention in the literature. This is a fundamental variable to understand circuit dynamics of networks subserving emotion. In this study we put to test a modified "valence" hypothesis of emotion processing, considering that sadness and happiness are processed by each hemisphere in relation to dominance for language and handedness. Mood induction and language activation during functional magnetic resonance imaging (fMRI) were used in 20 right-handed and 20 nonright-handed subjects, focusing on interconnected regions known to play critical roles in affective responses: subgenual cingulate cortex, amygdala, and anterior insular cortex. We observed a consistent relationship between lateralization of affective processing, motor dexterity, and language in individuals with clear right-handedness. Sadness induces a greater activation of right-hemisphere cortical structures in right-handed, left-dominant individuals, which is not evident in nonright-handed subjects who show no consistent hemispheric dominance for language. In anterior insula, right-handed individuals displayed reciprocal activation of either hemisphere depending upon mood valence, whereas amygdala activation was predominantly left-sided regardless of mood valence. Nonright-handed individuals exhibited less consistent brain lateralization of affective processing regardless of language and motor dexterity lateralization. In contrast with traditional views on emotion processing lateralization, hemispheric specialization in affective responses is not a unitary process but is specific to the brain structure being activated.

Cluster B personality symptoms in persons at genetic risk for schizophrenia are associated with social competence and activation of the right temporo-parietal junction during emotion processing.

Personality disorders are common in nonpsychotic siblings of patients with schizophrenia, and some personality traits in this group may be associated with an increased risk for full-blown psychosis. We sought to establish if faulty right-hemisphere activation induced by social cognitive tasks, as previously described in patients with schizophrenia, is associated with specific personality symptoms in their unaffected siblings. We observed that cluster B personality symptoms in this group were inversely related to activation in the right temporo parietal junction (rTPJ, a structure critical in social cognitive processing) in response to a basic emotion processing task and also to social competence, whereas in contrast to our initial hypothesis, cluster A traits were not associated with right hemisphere activation during emotion processing or with social competence. These findings suggest the existence of clinical traits in at-risk individuals which share a common neurobiological substrate with schizophrenia, in regards to social performance.